Inflammatory cytokines are deeply involved in the causes of inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, ulcerative colitis and Crohn's disease. Therefore, in therapeutic methods for these inflammatory diseases, inactivation of inflammatory cytokines by administration of a biologic such as a low-molecular-weight pharmaceutical or antibody has been attempted. On the other hand, to solve problems such as the increasing cost and induction of an unexpected immune reaction in such pharmacotherapies, therapies by extracorporeal circulation of blood using a column filled with a material having affinity to inflammatory cytokines have been developed in recent years.
As materials having affinity to inflammatory cytokines, adsorptive carriers prepared by immobilizing a functional group comprising an amino group derived from polyamine or the like on the surface of a water-insoluble carrier are known (JP 4591974 B and JP 2006-272075 A). Further, a multifunctional adsorptive carrier that enables adsorptive removal of not only inflammatory cytokines but also activated leukocytes from blood, which carrier is in the form of a fiber and has a diameter within a certain range, is known (JP 2006-312804 A).
Preparation of such a conventional carrier for adsorption of inflammatory cytokines requires a multistep process wherein, for example, polystyrene is first reacted with N-methylol -α-chloroacetamide for introduction of a reactive functional group, and polyamine is then immobilized to the reactive functional group by covalent bonding, to construct a desired functional group on the surface of a water-insoluble carrier. It has been suggested that the functional group immobilized on the surface of the water-insoluble carrier preferably comprises a functional group capable of hydrogen bonding such as a urea bond, thiourea bond and/or amide group. Further, for the purpose of giving solvent resistance and heat resistance to the obtained carrier, cross-linking between benzene rings derived from polystyrene is performed using paraformaldehyde.
However, since a urea bond, thiourea bond and amide group may be hydrolyzed at high temperature, it has been difficult to secure high adsorption capacity by contribution of these functional groups while securing heat resistance of the carrier. Further, although the problem of heat resistance is reduced by cross-linking between benzene rings, the cross-linking reaction and the introduction of a reactive functional group may compete with each other when these are carried out at the same time, resulting in inhibition of the introduction of a reactive functional group. Hence, in a decreased adsorption capacity, and it has also been pointed out that there is the risk of production of unexpected by-products in such a case. The cross-linking reaction may be carried out as a separate step to avoid the reaction competition, but this increases the number of steps and requires large amounts of various reagents, so that this is not an effective solution at present.
It could therefore be helpful to provide an adsorptive carrier having remarkable blood component-adsorbing capacity, especially inflammatory cytokine-adsorbing capacity, irrespective of whether the carrier has an amide group and/or the like, which carrier also has high solvent resistance and heat resistance. It could also be helpful to provide a method of producing an adsorptive carrier, wherein introduction of a desired functional group on the surface of the carrier and cross-linking between aromatic rings can be achieved by a single step.